多基因及miRNA网络调控下丙戊酸个体化用药研究

项目名称： 多基因及miRNA网络调控下丙戊酸个体化用药研究

项目编号： No.81473283

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王雪丁

作者单位： 中山大学

项目金额： 80万元

中文摘要： 癫痫是神经系统最常见疾病之一，丙戊酸（VPA）是经典抗癫痫药物，但其治疗窗窄、个体差异大困扰着临床用药。虽TDM在一定程度上能指导用药，但其存在显著滞后性。本实验室3年来对癫痫者使用VPA显著个体差异的研究表明，其主要代谢酶遗传多态性只能解释25%的药动学个体差异。网络药理学提示我们必须用网络的观念才有可能阐明药物反应个体差异机制。本人已在国家自然基金（30873025）资助下，在细胞及人体水平对CYP3A4及上游调控因子PXR等的基因多态性对药物代谢的影响、表观遗传学水平的调控因子mir-148等对不同靶基因的调控作用进行了研究。本课题将在前期研究基础上，探索更广泛的核受体遗传变异及相关miRNA组成的调控网络对VPA药物反应的影响，结合其药理作用新靶点NPY通路遗传多态性，更全面地筛查与VPA药动学和药效学 相关的影响因素，找出具临床意义的生物标志物，建立剂量预测方程并通过临床验证

中文关键词： 丙戊酸；核受体；微小RNA；调控网络；个体化用药

英文摘要： Epilepsy is one of the most common forms of nervous system diseases. Valproic acid (2-propylpentanoic acid, VPA) is the first-line agent for epilepsy, but VPA treatment is challenging due to its narrow therapeutic index and marked inter-individual variation in drug response. Therapeutic drug monitoring (TDM), to some extent, can be the instruction for clinical treatment, but the hysteretic nature of TDM limit its application in the adjustment of dosage regimen. The study carried out in our lab in the past 3 years focusing on the interviriability in epileptic patients treated with VPA showed that genetic polymorphisms in the metabolic enzymes involved accounted for only 25% of the inter-individual pharmacokinetic variation. Network pharmacology prompted us to confirme that the mechanism of inter-individual variation in drug response could be explained extensively by Network. Funded by NSFC (No.30873025), we have explored the effects of genetic polymorphisms in CYP3A4 and in the upstream regulator PXR on the drug metabolism in both cells and volunteers,studied the regulation of different target genes by epigenetic regulators such as mir-148. Based on the previous research，in the present program we are going to thoroughly screen the factors that affect the pharmacokinetics and the pharmacodynamics of VPA by investigating the effect of the more comprehensive genetic mutations in nuclear receptors (PXR/RXR/FXR/CAR etc.) and the blood concentrations of miRNAs predicted by bioinformatic softwares, and the regulatory network comprising of nuclear receptors, metabolic enzymes and transporter, and drug targets (neuropeptide Y and leptin,etc) and associated miRNAs on VPA response, therefore identifying biomarkers with clinical significance, and ultimately developing a dosing algorithm verified by prospecitve clinical trials.

英文关键词： valproic acid;nuclear receptor;microRNA;regulatory network;Personalized